Introduction: Emerging pathogens have a unique potential to be weaponized as bioterrorism agents because most humans have no immunity to such infections. The human response to these pathogens varies from aborted infection to overwhelming disease and death. This variation is determined by both environmental factors and host genetic factors (i.e. susceptibility alleles). A significant gap in our knowledge is that most of these genetic factors are unknown. Our goal is to identify alleles influencing susceptibility to severe West Nile virus (WNV) disease using a candidate gene approach. Such alleles must be functionally different than wild-type alleles, and thus likely to have been subject to natural selection[unreadable]the effects of which can be inferred from the pattern of variation in a gene. Thus, to increase the power of our approach we will first assess patterns of variation in each candidate gene and use these data to 1) find functional alleles, 2) determine which alleles will be most useful in association studies, and 3) identify alleles that influence susceptibility to severe WNV disease in a WNV cohort. To weight the odds of success in our favor, we will analyze genes that have been found in animal models or in vitro to influence WNV disease. Identifying alleles associated with WNV disease will facilitate the development of prognostic tests, vaccines, and therapeutics; and provide insights about how to find susceptibility alleles for other emerging pathogens. Project interactions: This project will closely interact with several other RCE projects and centers. WNV case ascertainment will be facilitated by Drs. Lyle Peterson (CDC-DVBID) and Franklyn Judson (Denver Public Health). Genes influencing murine WNV disease found by Drs. Morrey (II.G.1) and Kedl (II.C.6) will be studied in the human WNV cohort, and like-wise, the function of variants associated with human WNV disease can be studied in the WNV mouse model developed by Dr. Kedl (II.C.6). The WNV cohort we develop will provide a resource for testing new diagnostic systems developed by Dr. Corcoran (II.1.1).